Camelid single-domain antibody directed against phosphorylated TAU proteins and methods for producing conjugates thereof

A phosphorylation, domain technology, used in chemical instruments and methods, immunoglobulins, biomaterial analysis, etc.

Active Publication Date: 2017-02-22
F HOFFMANN LA ROCHE & CO AG +3
View PDF8 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Additionally, the small size results in rapid tissue penetration

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Camelid single-domain antibody directed against phosphorylated TAU proteins and methods for producing conjugates thereof
  • Camelid single-domain antibody directed against phosphorylated TAU proteins and methods for producing conjugates thereof
  • Camelid single-domain antibody directed against phosphorylated TAU proteins and methods for producing conjugates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0234] Example 1: Generation of conjugation to ALEXA anti-phosphorylated TAU VHH and its body In vitro / in vivo evaluation

[0235] Materials and methods

[0236] 1. Production, selection and purification of anti-tau-specific VHH (Tau-A2)

[0237] 1.1 Preparation of antigen and induction of humoral immune response in alpaca

[0238] subjects

[0239] Human cortical brain tissues from AD patients (Braak stages V and VI) were obtained from the NeuroCEB Brain Bank. The bank is linked to the Brain Donation Program, run by the consortium of patients associations (including the French Alzheimer's Association) and declared by the French Ministry of Research and Universities as required by French law . Express written consent was obtained for brain donation in accordance with French bioethics law.

[0240] Tissue extraction was performed according to Mercken et al. (1992 Acta Neuropathol., 84, 265-272). Cortex from AD brains (0.2 g) was homogenized in 10 volumes of ...

Embodiment II

[0328] Example II: Synthesis of a variant of TAU-A2-SH: TAU-A2VAR-SH

[0329] VHH Tau-A2 specifically detects phosphorylated Tau, but its production level is rather low, averaging 150 μg / L, and tends to aggregate. It is therefore desirable to provide a variant of VHH Tau-A2 with improved properties.

[0330] The 2 hydrophobic amino acids located in the 2 hydrophobic regions of VHH Tau-A2-SH shown in SEQ ID NO.14 are mutated: isoleucine at position 76 is replaced by glycine (I76G), and vale at position 110 Amino acid is replaced by glycine (V110G) ( Figure 10 ). These mutations increase the hydrophilicity of the VHH, with an increased GRAVY index ranging from -0.280 for Tau-A2-SH to -0.365 for the variants (GRAVY or Grand average hydrophilicity index indicates the solubility of the protein: positive GRAVY (hydrophobic ), negative GRAVY (hydrophilic)). Glutamine at position 26 was also mutated to glutamic acid (Q26E), and aspartic acid (D) and valine (V) were added betwee...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
molecular weightaaaaaaaaaa
Login to view more

Abstract

The present invention relates to variable domains of a camelid heavy-chain antibodies directed against a phosphorylated tau protein and conjugates thereof. The present invention also relates to the use of these domains or conjugates for treating or diagnosing disorders mediated by neurofibrillary tangles, neuropil threads or dystrophic neurites, such as tauopathies.

Description

technical field [0001] The present invention relates to antibodies against phosphorylated tau protein and conjugates thereof. The present invention also relates to the use of these antibody conjugates for treating or diagnosing diseases mediated by phosphorylated tau protein. Background technique [0002] Approximately 70% of all dementia cases are due to Alzheimer's disease (AD), which is associated with selective damage to brain regions and neural circuits important for cognition. Alzheimer's disease is characterized by neurofibrillary tangles (NFTs), especially in the pyramidal neurons of the hippocampus, as well as massive amyloid plaques. [0003] Ultrastructural studies of AD brain specimens have shown that NFT is mainly composed of paired helical filaments (PHF), and these filaments are pairs of axially opposite fibrils with a diameter of about 10 nm and regular periodic helical stereotypes of 65 nm. Conformation (Kidd 1963Nature, 197, 192–3; et al. 1976 J Neurol ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/18A61K49/16A61K51/10
CPCA61K49/16A61K51/10C07K2317/22C07K2317/569C07K16/18A61P25/00A61P25/04A61P25/08A61P25/24A61P25/28A61P29/00A61K47/6843A61K47/6803G01N33/6896A61K49/0041A61K49/0058C07K2317/34G01N2333/47G01N2440/14G01N2800/2821
Inventor P·拉费S·巴伊B·德拉图尔M·德南C·杜依卡尔特李腾飞M·范德斯奎勒C·捷克F·格鲁宁格
Owner F HOFFMANN LA ROCHE & CO AG
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap